Accurately estimating glomerular filtration rate (GFR) is central to the study, prevention and treatment of chronic kidney disease (CKD). Serum cystatin C (CysC) may provide a better estimate of GFR than serum creatinine (sCr). In order to determine if CysC is better, a large study using uniform measurements of sCr, CysC, and a wide range of participant characteristics is needed. This will allow for the development of an equation for estimating GFR from CysC and for rigorous evaluation of the newly developed equation for CysC as compared to equations using sCr to estimate GFR. In Phase I (1 year R21), we will (1) assay CysC in frozen serum from a large multi-ethnic group of clinical trial participants and screenees (n=1668 AASK and 1041 MDRD study baseline and 633 AASK and 433 MDRD study 2-year follow-up visits) with standardized measurements of 125I-iothalamate GFR, sCr and CysC in a single laboratory; (2) develop an equation to estimate GFR from CysC; and (3) compare this equation to equations using sCr with respect to bias, precision and simplicity and assess its generalizability. We will use the MDRD 4-variable equation which includes sCr, age, sex, and race as a benchmark with which to compare the newly developed CysC equation. We propose to proceed to the R33 phase if the newly developed CysC equation does not require adjustment for age, sex, race, body composition or diet, and this equation shows better accuracy overall or in predefined subgroups as compared to the MDRD 4-variable equation. In Phase II (2 year R33), we will (1) assay CysC in frozen serum from 8,804 NHANES III (1988-1994) and 5,135 NHANES 1999-2000 participants age 12+ years; (2) estimate the prevalence of decreased kidney function and CKD in these surveys using the newly developed CysC equation for estimating GFR; and (3) compare estimates from the CysC equation and sCr equations. We hypothesize that the overall prevalence of decreased kidney function and chronic kidney disease (CKD) will be similar, but differences will exist for specific subgroups. These CysC data will be made publicly available allowing for improved study of estimated kidney function, its correlates and consequences in these NHANES surveys. Estimation of kidney function has been at the core of most clinical trials of the progression of CKD and estimates of the high prevalence of decreased kidney function in the US population have been influential. This large and rigorous evaluation of whether CysC can improve estimation of GFR in individuals and the population should have a high impact on research, practice and policy related to CKD--meeting the goals of this program announcement.